Fundación para la Investigación Biomédica, Hospital Universitario de Getafe, Getafe, Spain.
Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain.
Free Radic Biol Med. 2013 Dec;65:380-401. doi: 10.1016/j.freeradbiomed.2013.07.003. Epub 2013 Jul 10.
Vascular aging, a determinant factor for cardiovascular disease and health status in the elderly, is now viewed as a modifiable risk factor. Impaired endothelial vasodilation is a early hallmark of arterial aging that precedes the clinical manifestations of vascular dysfunction, the first step to cardiovascular disease and influencing vascular outcomes in the elderly. Accordingly, the preservation of endothelial function is thought to be an essential determinant of healthy aging. With special attention on the effects of aging on the endothelial function, this review is focused on the two main mechanisms of aging-related endothelial dysfunction: oxidative stress and inflammation. Aging vasculature generates an excess of the reactive oxygen species (ROS), superoxide and hydrogen peroxide, that compromise the vasodilatory activity of nitric oxide (NO) and facilitate the formation of the deleterious radical, peroxynitrite. Main sources of ROS are mitochondrial respiratory chain and NADPH oxidases, although NOS uncoupling could also account for ROS generation. In addition, reduced antioxidant response mediated by erythroid-2-related factor-2 (Nrf2) and downregulation of mitochondrial manganese superoxide dismutase (SOD2) contributes to the establishment of chronic oxidative stress in aged vessels. This is accompanied by a chronic low-grade inflammatory phenotype that participates in defective endothelial vasodilation. The redox-sensitive transcription factor, nuclear factor-κB (NF-κB), is upregulated in vascular cells from old subjects and drives a proinflammatory shift that feedbacks oxidative stress. This chronic NF-κB activation is contributed by increased angiotensin-II signaling and downregulated sirtuins and precludes adequate cellular response to acute ROS generation. Interventions targeted to recover endogenous antioxidant capacity and cellular stress response rather than exogenous antioxidants could reverse oxidative stress-inflammation vicious cycle in vascular aging. Lifestyle attitudes such as caloric restriction and exercise training appear as effective ways to overcome defective antioxidant response and inflammation, favoring successful vascular aging and decreasing the risk for cardiovascular disease.
血管老化是心血管疾病和老年人健康状况的决定因素，现在被认为是一种可改变的危险因素。内皮血管舒张功能受损是动脉老化的早期标志，先于血管功能障碍的临床表现，而血管功能障碍是心血管疾病的第一步，也会影响老年人的血管预后。因此，保持内皮功能被认为是健康衰老的一个重要决定因素。本文特别关注衰老对内皮功能的影响，重点介绍了与衰老相关的内皮功能障碍的两个主要机制：氧化应激和炎症。衰老的血管会产生过多的活性氧（ROS）、超氧化物和过氧化氢，从而损害一氧化氮（NO）的血管舒张活性，并促进有害自由基过氧亚硝酸盐的形成。ROS 的主要来源是线粒体呼吸链和 NADPH 氧化酶，尽管 NOS 解偶联也可能导致 ROS 的产生。此外，血红素加氧酶-1 相关因子-2（Nrf2）介导的抗氧化反应减少和线粒体锰超氧化物歧化酶（SOD2）下调导致衰老血管中慢性氧化应激的建立。这伴随着慢性低度炎症表型，参与了内皮血管舒张功能障碍。氧化还原敏感转录因子核因子-κB（NF-κB）在老年受试者的血管细胞中上调，并驱动导致氧化应激的促炎转变。这种慢性 NF-κB 激活是由血管紧张素 II 信号增加和沉默信息调节因子下调引起的，并阻止了细胞对急性 ROS 产生的适当反应。针对恢复内源性抗氧化能力和细胞应激反应的干预措施而不是外源性抗氧化剂，可能会逆转血管老化中的氧化应激-炎症恶性循环。生活方式态度，如热量限制和运动训练，似乎是克服抗氧化反应和炎症缺陷的有效方法，有利于成功的血管老化，并降低心血管疾病的风险。
